Yeast response to the expression of human proteins involved in proteinopathies

The yeast S. cerevisiae has contributed significantly to the understanding of the basic biology of a variety of eukaryotic cellular processes and it is an established model organism for the analysis of evolutionarily conserved cellular pathways relevant for protein degradation, including human neurotoxic proteins, aging and cell death [1]. FENIB (Familial encephalopathy with neuroserpin inclusion bodies) is a rare neurodegenerative disease with autosomal dominant inheritance caused by different mutations in neuroserpin gene (NS1) that promote polymerization and intracellular deposition of this protein causing both loss of function (loss of the functional protein) and gain of function (toxicity of the aggregated protein). The severity of the phenotype depends on the specific mutation, and the toxicity correlate with the capacity to form aggregates. Despite several studies conducted so far on different cell models there is not a resolving cure for this disease [2]. We aim to use S. cerevisiae as a host for the expression of NS wild type and mutated genes with the final purpose to identify the molecular mechanisms of cytotoxicity and possible new targets for therapeutic intervention. In this context, humanized yeast models could be a powerful tool for accelerating and facilitating the identification of cellular players, bio-molecular pathways involved in FENIB beginning and the use this modified yeast to screen for new drugs for neurodegenerative diseases treatments. References [1] Fruhmann, G et al.,. (2017). Mech Ageing Dev. Jan;161(Pt B):288-305. [2] Guadagno, NA et al., (2017). Neurobiology of Disease, 103:32-44